1. Field of the Invention
The present invention relates to an immunosuppressive agent, particularly to an immunosuppressive agent comprising a selective inhibitor of the activated T cells, as an active ingredient. More particularly, the present invention relates to a therapeutic agent for treating diseases due to abnormal immune response induced by the activated T cells, such as rejection for organ transplantation, graft versus host disease by bone marrow (hematopoietic stem cell) transplantation, autoimmune disease, inflammatory reaction, fibrosis or dysfunction caused by autoimmune disease or related disease thereof with tissue injury or infection, or allergic disease.
2. Description of the Prior Art
Immune system of an organism has been developed with surveillance and defense mechanism by recognition and elimination of pathogenic foreign microorganisms such as bacteria and viruses. Therefore, the organism distinguishes own cells or tissue (self-antigens) from foreign microorganism (nonself-antigens), and does not respond to the self-antigens, or respond to them having the failure to mount immune response (immunological tolerance). Accordingly, the organism has developed an acquired immunity to eliminate nonself-antigens immediately and efficiency.
In the immune system, T cells (T lymphocytes) play an important role. The naxc3xafve CD4T cells in the periphery are activated by receiving both the signal of antigen from antigen-presenting cells through a T cell receptor, and signals of other costimulatory molecules. Then, they proliferate secreting IL-2, i.e., T cell growth factor (Thp). The Thp differentiate to Th0 cells, then, separate to Th1 cells or Th2 cells. These cells further proliferate, produce a various kinds of cytokines and introduce a cytopathic effect.
When an abnormal reaction happens in this series of immune response, lymphocytes, especially T cells, strongly respond to self-antigens, and could generate a tissue injury. This state is called as autoimmune disease. One of the causes which trigger the abnormal immune response is that normal immune response against viruses or bacteria is changed to immune response against self-antigens by some kind of system. The tissue injury or infection induced by autoimmune disease, introduce a various kinds of inflammatory reaction, fibrosis of tissue or dysfunction, so on.
Although the rejection for organ transplantation or graft versus host disease by bone marrow (hematopoietic stem cell) transplantation is a normal immune response reaction, it is therapeutically desired to inhibit it. The mechanism of this immune response is basically the same, and the activated T cells play main role in the reaction.
Recently, the role of the activated T cells in allergic disease has drawn attention. Namely, it has been evidenced that cytokines such as IL-4 and IL-5 produced mainly by the activated Th2 cells, activate mast cells or eosinophile to induce immediate hypersensitivity, and interferon-xcex3 (IFN-xcex3) produced mainly by Th1 cells induce delayed-type hypersensitivity.
Therefore, the therapeutic agent having selective inhibiting activity of the activated T cells for treatment of autoimmune disease, immunity of transplantation, chronic active-typed immunological inflammatory reaction caused by the disease mentioned before, and allergy disease has been desired.
Under these circumstances, therapeutic method to control the mediators in T cells activating mechanism has been studied. Among them, strong suppressive effect against T cells using cyclosporine or FK-506, anti-cytokine therapy, anti-adhesion molecule (activation related molecules) therapy, or monoclonal antibody has drawn attention. However, these compounds have not the potential selectivity against the activated T cells, similar to glucocorticoids used heretofore, and the problem of side effects still remains.
Incidentally, the autoimmune disease is systemic disease that may occur in any of organs. Furthermore, in accordance with the development of the organ transplantation and hematopoietic stem cell transplantation, the problem of rejection for transplantation and graft versus host disease is expected to increase. Additionally, allergic disease is called as xe2x80x9ccivilized diseasexe2x80x9d, and there are great number of patients who are suffering from it, due to the difficulty of curing from the disease perfectly.
There are many diseases in which the activated T cells play main role, thus the development of the effective therapeutic agent for treatment thereof is desired. Nevertheless, there is no such an agent, at the present time, which selectively inhibit the activated T cells for the treatment of diseases cased by the activated T cells.
Accordingly, the object of the present invention is to provide an effective immunosuppressive agent having a selective inhibiting activity of the activated T cells, with low side effects. More particularly, the object of the present invention is to provide the therapeutic agent for treating autoimmune disease, inflammatory reaction occurred in autoimmune disease or related diseases thereof with tissue injury or infection, fibrosis, dysfunction, rejection for organ transplantation, graft versus host disease by bone marrow (hematpoietic stem cell) transplantation, and allergic disease.
In order to solve the problems, therefore, the present inventors have found out the compounds having selectively inhibiting activity of the activated T cells, by means of the mechanism of the selective induction of apoptosis in the activated T cells. Further, the present inventors have found out that these compounds have potential activities for preventing or controlling the diseases caused by activated T cells.
Accordingly, one aspect of the present invention is to provide the immunosuppressive agent comprising a selective inhibitor of the activated T cells, as active ingredient.
In the present invention, the activated T cells are those which proliferate by producing and secreting a various kinds of cytokines, then cause a series of the immune response.
Thus, the present invention is characterized by inhibition of the activated T cells by inducing selective apoptosis, and preventing or treating the diseases resulted from the abnormal immune response caused by these activated T cells.
Therefore, the specific aspect of the present immunosuppressive agent is to provide the agent for treating rejection for organ transplantation, graft versus host disease by bone marrow (hematopoietic stem cell) transplantation, autoimmune disease, inflammatory reaction caused by autoimmune disease or related disease thereof with tissue injury or infection, fibrosis, dysfunction or allergic disease.
The autoimmune diseases to be prevented and treated effectively by the immunosuppressive agent of the present invention are, for example, autoimmune hepatitis, rheumatoid arthritis, insulin-dependent diabetes mellitus (IDDM), ulcerative colitis, multiple sclerosis (MS), scleroderma, myasthenia gravis, multiple myositis/dermatomyositis, Hashimoto""s disease, autoimmune hypocytosis, Sjxc3x6gren""s syndrome, angitis syndrome or systemic lupus erythematosus, and so on.
In still another embodiment of the present invention, the allergic disease is, for example, bronchial asthma, allergic rhinitis, atopic dermatitis, urticaria, pollinosis, and so on.
The present immunosuppressive agent is therapeutically useful for preventing or treating the diseases by selectively inhibiting the activated T cells, with low side effects.
The compound, as the active ingredient of the present invention, can be selected by the measurement of apoptosis induction activity to the activated T cells for example, that isolated from mice with delayed-type hypersensitivity (DTH) reaction, as described later.
Based on the present inventor""s investigation, they have found out the following flavanoids or chromones represented by the formula (I): 
wherein,
R is hydrogen atom or a phenyl group which may be substituted with one or two hydroxy groups,
Rha is xcex1-L-rhamnose residue, and dotted line indicates with or without double bond.
Accordingly, the another aspect of the present invention is to provide the immunosuppressive agent comprising flavanoids or chromones represented by the formula (I) as active ingredient.
Among them, chromones of formula (I), in which R is hydrogen atom, or flavanoides of formula (I), in which R is 4-hydroxyphenyl, 3,4-dihydroxypheny, or 3,5-dihydroxypheny are preferably used. More specifically, smitilbin of the formula (I-a), astilbin of the formula (I-b), engeletin of the formula (I-c) or eucryphin of the formula (I-d) is more preferable. 
Some of the flavanoids or chromones of the present invention is known compound; however, their anti-inflammatory activities had been only examined, and their improvement activities of abnormal immune reaction have not been known. Smitilbin of the formula (I-a) is new compound discovered by the present inventors. Thus, still another embodiment of the present invention is to provide smitilbin of the formula (I-a) itself.